Pulmonary fibrosis is a devastating disorder that affects five million people worldwide. However, the actual numbers may be significantly higher as a possible consequence of misdiagnosis. Typically, patients develop pulmonary fibrosis in their forties and fifties with symptoms that include shortness of breath, chronic cough, fatigue, loss of appetite and rapid weight loss. The mean survival time following diagnosis is less than 5 years (Giri, 2003). Pulmonary fibrosis is not seen as a separate entity but develops usually in the context of environmental exposures or as an accompaniment of a syndrome. Common causes are exposure to asbestos, metal dusts or organic substances, sarcoidosis (a disease characterized by the formation of granulomas), exposure to medical drugs and radiation. Often pulmonary fibrosis is associated with connective tissue or collagen diseases such as rheumatoid arthritis and scleroderma (Giri, 2003).
Pathologically, the disease is characterized by chronic inflammation and collagen production within fibroblastic foci in the lung.
Myofibroblasts, a distinguishing feature of fibroblastic foci, are thought to arise from local activation of parenchymal fibroblasts by transforming growth factor β (TGF-β) stimulation and are historically considered to be the collagen-producing cell in fibrotic lesions (Selman and Pardo, 2003); in addition, CTGF (connective tissue growth factor) is considered a very important factor and is required for differentiation and collagen gene expression. However, recent findings have questioned this fundamental concept and suggested a hematopoietic origin of the pathological fibroblasts (Hashimoto et al., 2004). The disease typically proceeds with scarring of the lung and the alveoli which become lined by fibrotic tissue. When the scar forms, the tissue becomes thicker causing an irreversible loss in efficiency of the tissue's ability to transfer oxygen into the bloodstream (Gross and Hunninghake, 2001).
Several growth factors have been implicated in the pathogenesis of pulmonary fibrosis. These factors have been identified by virtue of their ability to stimulate fibroblast division and extracellular matrix (ECM) production, as well as their presence in the lungs and lung fluids of patients or animals with fibrotic lung disease. These growth factors include TGF-β, insulin-like growth factor (IGF)-I, platelet-derived growth factor (PDGF), members of the fibroblast growth factor (FGF) family and keratinocyte growth factor (KGF) (Krein and Winston, 2002).
There are currently no effective treatments or a cure for pulmonary fibrosis. The pharmacological agents designed to treat lung scarring are still in the experimental phase. Although traditional theories have postulated that it might be an autoimmune disorder, the treatments intended to suppress inflammation have only limited success in reducing the fibrotic progress (Giri, 2003). Since pulmonary fibrosis is a very complex disease, the prediction of longevity of patients after diagnosis varies greatly.
It is still a matter of debate if pulmonary fibrosis is primarily caused by chronic inflammation (Gross and Hunninghake, 2001). Originally, experimental evidence suggested that fibrotic lung diseases are inflammatory disorders at their inception. For example, pulmonary fibrosis develops in mice with ectopic expression of the inflammatory mediator tumor necrosis factor α (TNF-α) in the lung (Miyazaki et al., 1995). Additionally, in a bleomycin model of pulmonary fibrosis in the mouse, the fibrosis is preceded by profound inflammation, including the production of high levels of TNF-α (Piguet et al., 1989). Importantly, TNF-α-deficient or TNF-α receptor-deficient mice are resistant against bleomycin-induced pulmonary fibrosis (Ortiz et al., 1998; Piguet et al., 1997). These results led to the assumption that fibrosis might be avoided when the inflammatory cascade is interrupted before irreversible tissue injury occurred. Thus, this theory explains the initial enthusiasm for corticosteroid and cytotoxic therapy of pulmonary fibrosis. However, it is now clear that the current anti-inflammatory therapy provides little benefit (Giri, 2003). Therefore, some studies have attempted to show that fibrotic lung disorder is not an inflammatory disorder. For example, development of fibrotic lung disease can be triggered by adenoviral transfer of TGF-β to the lungs of animals with only a transient inflammatory response. These new insights suggest that pulmonary fibrosis results from sequential lung injury with a subsequent wound healing response rather than chronic injury. Therefore, a therapeutic strategy based on modification of fibroblast replication and matrix deposition is established. However, no beneficial clinical effect was seen in patients after colchicine treatment (interferes with intracellular collagen processing) or penicillamine treatment (collagen cross-link inhibitor). Other agents that are in experimental trials to block fibrogenesis include pirfenidone, interferon γ or antibodies against TGF-β signaling (Giri, 2003).
Consequently, there is a need for an efficient and reliable animal model for the study of fibrotic diseases, e.g. pulmonary fibrosis, and for testing drug candidates for the treatment of such disorders.